Supplementary Figure 1: Number of cancer cases and deaths across indications in 2020, Millions

PURPOSE:Breast cancer imposes a substantial disease burden on the Brazilian population. Furthermore, the potential unnecessary use of adjuvant chemotherapy exposes patients to risks and adverse effects without significant therapeutic benefits. The purpose of this study is to determine the extent to which genomic testing for treatment selection, particularly in early stages, is a cost-effective strategy for optimizing care, while minimizing costs and unnecessary interventions. METHODS:We estimated the economic impact of the Oncotype DX test to guide the decision about prescribing adjuvant chemotherapy. The model integrates a decision tree and a Markov model with transitions between the health states of recurrence-free survival, distant recurrence, acute myeloid leukemia, and death. The probabilities of distant recurrence were derived from the TAILORx and RxPONDER clinical trials, combined with local evidence regarding utility and overall survival estimates. The analysis was conducted from the perspective of the Brazilian private health care system, which covers about one quarter of the Brazilian population. Scenario and sensitivity analyses with Monte Carlo simulations were performed. RESULTS:Compared with clinicopathologic risk assessment alone, use of the Oncotype DX test for both node-negative (N0) and node-positive (N1) leads to an increase in quality-adjusted life-years (QALYs) at lower costs (0.15 QALYs and $-3,975.59 US dollars [USD]). The main impact drivers were chemotherapy costs, chemotherapy prescription probabilities, and Oncotype DX test cost. Considering the Brazilian official cost-effectiveness thresholds ($8,000.00 USD to $24,000.00 USD per QALY), the probabilistic sensitivity analysis indicated a high probability of the test being cost-effective across all analyzed scenarios and indications. CONCLUSION:Oncotype DX could be a cost-saving strategy in the Brazilian private health care perspective. Alternative scenarios and testing indications did not alter these conclusions.

For early-stage triple-negative breast cancer (TNBC), the KEYNOTE-522 trial established neoadjuvant pembrolizumab plus chemotherapy (CT), followed by adjuvant pembrolizumab, as the standard of care. Nevertheless, uncertainties remain on how to integrate this regimen with other adjuvant therapies such as capecitabine or olaparib. This study evaluated real-world treatment patterns and safety of adjuvant therapies following neoadjuvant chemoimmunotherapy. The Neo-Real study includes patients with TNBC treated with neoadjuvant pembrolizumab plus CT in Brazil and Argentina. This study describes real-world adjuvant treatment patterns and safety; survival outcomes are not reported in this analysis. Among 726 patients included, 692 underwent surgery, and 62.9

610 Background: Neoadjuvant pembrolizumab combined with chemotherapy is the standard of care for early-stage triple-negative breast cancer (TNBC) based on KEYNOTE-522, improving pathologic complete response (pCR) and event-free survival (EFS). Emerging data suggest that immunotherapy timing may influence oncologic outcomes; however, evidence in early-stage TNBC and in combination regimens is limited. We conducted an exploratory real-world analysis to evaluate the association between infusion timing and clinical outcomes. Methods: Neo-Real/GBECAM-0123 is a multicenter real-world cohort including patients with early-stage TNBC treated with neoadjuvant pembrolizumab-based chemotherapy in Brazil and Argentina. In this analysis, patients treated between 2019 and 2024 with available infusion timing data were included. Infusion timing was classified as Early (≤20% of pembrolizumab infusions initiated at or after 14:00) or Late (>20% initiated at or after 14:00). The primary endpoint was pCR (ypT0/Tis ypN0). Secondary endpoints included EFS, defined according to KEYNOTE-522 criteria. Sensitivity analyses using timing definitions were performed. Results: Among 419 patients with available infusion timing data (Early: n=265; Late: n=154); 385 underwent surgery and were evaluable for pCR. Baseline clinicopathologic characteristics were largely balanced between groups, although stage III disease was numerically more frequent in the Early group (30.9% vs 23.6%, p=0.134). Treatment features, including use of dose-dense chemotherapy and number of neoadjuvant pembrolizumab cycles (median 8 in both groups), were similar. pCR rates did not differ according to infusion timing (Early: 62.5% vs Late: 64.1%; p=0.827). Late infusion timing was associated with improved EFS, with a 2-year EFS of 90.7% versus 82.7% (p=0.013). In multivariable Cox regression adjusting for age, clinical stage, pathologic response, tumor grade, histology, and number of neoadjuvant pembrolizumab cycles, Late infusion timing remained associated with improved EFS (HR 0.34; 95% CI 0.15–0.80; p=0.013). Sensitivity and subgroup analyses, including evaluation of the timing of the first pembrolizumab infusion using an earlier cut-off (11:00), as well as analyses by histology, clinical stage, and pathologic response, yielded consistent results. Conclusions: In this exploratory real-world analysis of patients with early-stage TNBC treated with neoadjuvant pembrolizumab-based chemotherapy, infusion timing was not associated with pCR. However, later infusion timing was associated with improved EFS. These findings contrast with observations reported in other tumor types and underscore the need for further studies to clarify the impact of immune checkpoint inhibitor infusion timing on clinical outcomes in TNBC.

The KEYNOTE-522 regimen is the standard of care for stage II-III triple-negative breast cancer (TNBC). However, older patients were underrepresented in the pivotal trial. We evaluated the effectiveness and safety of this regimen in patients aged ≥65 years enrolled in the Neo-Real/GBECAM-0123 multicenter real-world study conducted across institutions in Brazil and Argentina. Among 724 patients, 80 (11%) were aged ≥65 years and presented distinct baseline characteristics, including lower frequencies of grade 3 tumors, Ki67 ≥ 50%, and germline BRCA1/2 mutations, alongside a higher prevalence of impaired performance status. The pathologic complete response (pCR) rate in older patients was 54.9% in comparison with 64.5% in younger patients, although age was not independently associated with pCR in multivariable analysis, including other relevant baseline variables. Older patients experienced a significantly higher toxicity burden, with increased rates of treatment discontinuation, dose reductions, treatment delays, hospitalizations, and grade ≥3 neutropenia. Taken together, these data indicate that older patients with TNBC harbor distinct biological and clinical features with numerically lower pCR rates, and that the increased toxicity burden underscores the need for personalized treatment strategies and dedicated research in this population.

Special histologic subtypes of triple-negative breast cancer (TNBC) are biologically distinct, yet their outcomes in the immunotherapy era remain undefined. We analyzed 823 patients with early-stage TNBC treated with pembrolizumab plus chemotherapy in the multicenter real-world Neo-Real/GBECAM-0123 cohort. Histologies included invasive carcinoma of no special type (NST; n = 762, 92.6%), metaplastic carcinoma (n = 26, 3.2%), triple-negative lobular carcinoma (n = 17, 2.1%), and other rare variants (n = 18, 2.2%). Metaplastic carcinoma demonstrated significantly lower pathological complete response (pCR) rates compared with NST (17.4% vs 65.4%; OR 0.14, 95% CI 0.04–0.44; p = 0.001), suggesting relative resistance to chemo-immunotherapy, with a numerical trend toward worse event-free survival (EFS) (HR 2.07, 95% CI 0.88–4.88; p = 0.094). Triple-negative lobular carcinoma achieved pCR rates comparable to NST (56.2%) but showed poorer 2-year EFS, with a significant association in the pre-surgical multivariable model (HR 4.25, 95% CI 1.50–12.06; p = 0.006), and a persistent trend after adjustment for pCR. This highlights the biological heterogeneity of TNBC and supports the investigation of histology-driven therapeutic strategies.

Tumor-infiltrating lymphocytes (TILs) are established prognostic and predictive biomarkers in early-stage triple-negative breast cancer (eTNBC), yet their role in patients treated with the KEYNOTE-522 (KN522) regimen remains underexplored. The Neo-Real/GBECAM-0123 study is a real-world cohort of patients with early-stage TNBC treated with pembrolizumab plus neoadjuvant chemotherapy across Brazil and Argentina since 2020; we evaluated baseline stromal TILs (<30%, 30–49%, or ≥50%) as predictors of pathologic complete response (pCR, primary endpoint) and event-free survival (EFS, secondary endpoint). Among 248 patients, TILs were <30% in 72.6%, 30–49% in 12.9%, and ≥50% in 14.5%. pCR rose with increasing TILs: 59%, 65.6%, and 91.4% (P = 0.001). In multivariable analysis, TILs ≥50% (OR 6.96, 95% CI 1.89–25.65, P = 0.004) and Ki-67 ≥ 50% (OR 4.89, 95% CI 2.31–10.33, P < 0.001) independently predicted pCR; virtually all patients with both TILs ≥50% and Ki-67 ≥ 50% achieved pCR (n = 26/27, 96.3%). Among patients with pCR, 2-year EFS was uniformly high across TIL groups (97.0%, 95.2%, 93.2%; P = 0.828); among those with residual disease, EFS trended higher with increasing TILs (73.3%, 90.0%, 100%; P = 0.350), non-significant. Baseline TILs, especially with Ki-67, emerged as a strong predictor of pCR in this real-world eTNBC cohort treated with KN522, supporting their systematic assessment in future studies.

PURPOSE:Oncotype DX (ODX) is a validated gene expression assay that provides prognostic and predictive information to guide adjuvant chemotherapy (ACT) decisions in hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer (eBC), including node-negative (N0) and 1-3 node-positive (N1) disease. In Brazil, limited access to gene expression signatures (GES) remains a barrier to individualized treatment decisions. METHODS:We conducted a multicenter retrospective study across nine Brazilian private cancer centers to evaluate clinicopathologic predictors of high genomic risk (ODX recurrence score [RS] >25) and to assess the clinical impact of ODX on ACT decision making. RESULTS:Between 2005 and 2024, 935 patients were included, with a notably higher representation of young (≤40 years: 10.9%) and premenopausal (40.7%) women than typically reported in randomized clinical trials. Ki-67 >20%, progesterone receptor (PR) expression ≤30%, and histologic grade 3 were independently associated with high RS in both univariable and multivariable analyses (all P <.001), with Ki-67 emerging as the strongest clinicopathologic predictor. Overall, ODX testing was associated with an estimated 12.6% absolute reduction in ACT recommendations, with substantial impact among postmenopausal patients with N1 disease (94% absolute reduction) and N0 patients older than 50 years with high clinical risk (65.2% absolute reduction). With a median follow-up of 4.8 years, the estimated 5-year real-world invasive disease-free survival and distant disease-free survival were 100% and 100% for those with RS <11, 98.2% and 99.4% for RS 11-25, and 90.9% and 92.5% for RS >25, respectively. CONCLUSION:In this data set, ODX demonstrated utility in guiding ACT decision making and supporting personalized treatment by reducing both overtreatment and undertreatment. In resource-constrained settings, surrogate markers such as Ki-67, PR expression, and histologic grade may serve as practical tools to guide risk-adapted clinical decisions.

Supplementary Figure 2: Number of cancer cases and deaths across geography in 2020, Millions

Supplementary Table 1: Authors and affiliations

PURPOSE/OBJECTIVE:To compare demographic characteristics, stage at diagnosis, treatment patterns, and survival outcomes of breast cancer patients treated in Brazil's public and private healthcare systems. MATERIALS AND METHODS:This retrospective cohort study analyzed data from the Fundação Oncocentro de São Paulo, including women diagnosed with invasive breast cancer between January 2000 and June 2020. Overall survival (OS) was estimated using Kaplan-Meier methods and log-rank tests. Prognostic factors were evaluated using Cox proportional hazards models. RESULTS:A total of 65,543 patients were included. Age distribution was similar between the public and private sectors. However, early-stage diagnoses (stages I and II) were significantly more frequent in the private sector (77.8%), whereas the public system had a higher proportion of patients diagnosed at advanced stages (67.8% in stages II and III) and with metastatic disease (11.1% vs. 5.3%). The proportion of patients receiving surgery and at least 2 adjuvant therapies (trimodal therapy) was comparable between sectors (46.6% private vs. 46.2% public). Survival analysis demonstrated consistently higher 5- and 10-year OS across all stages in the private sector. Ten-year OS by stage was: I-81.6% (private) versus 77.5% (public), P < .001; II-74.0% vs. 63.3%, P < .001; III-55.6% versus 39.6%, P < .001; IV-7.6% versus 6.4%, P = .306. Multivariate analysis identified treatment in the private sector, younger age at diagnosis, higher education level, receipt of trimodal therapy, and earlier stage as independent predictors of improved OS. CONCLUSION:Breast cancer patients treated in the public healthcare system in Brazil more often present with advanced disease, which is associated with inferior survival outcomes.

e12618 Background: Triple-negative breast cancer (TNBC) is the most immunogenic subtype and is highly prevalent among patients (pts) with germline BRCA1/2 mutations (gBRCAm). Regardless of mutation status, the current standard treatment for early-stage TNBC is chemotherapy combined with pembrolizumab, as per the KEYNOTE-522 protocol. Methods: Data were collected from pts diagnosed with early-stage TNBC treated according to the KEYNOTE-522 regimen at ten cancer centers from July 2020 to December 2024. Epidemiological data and treatment outcomes of pts with gBRCAm were compared to those with BRCA wild-type/unknown (BRCAwt). Results: A total of 413 pts were analyzed, of whom 320 (82%) underwent germline testing; 49 (12.7%) had a gBRCAm, including 45 (91%) with BRCA1 and 4 (9%) with BRCA2 mutations. Pts with gBRCAm were younger (median 39 vs. 44 years, P<0.001) and more likely to be premenopausal (80.8% vs. 65.6%, P=0.045) and have grade 3 tumors (91% vs. 80%, P=0.214) than BRCAwt pts. Stage II disease was the most common in both groups (71.4% vs. 70%, P=0.315). Regarding treatment, gBRCAm pts were more frequently treated with dose-dense AC (doxorubicin and cyclophosphamide) (66% vs. 54%, P=0.160) and underwent mastectomy more often (93.9% vs. 35.9%, P=0.001). Only 2% of gBRCAm pts experienced disease progression during neoadjuvant therapy compared to 5% of BRCAwt pts (P=0.491).Pathological complete response (pCR; ypT0-Tis ypN0) rates were 73% in gBRCAm pts compared to 61% in BRCAwt pts (P=0.114). Residual cancer burden (RCB) 0-1 occurred in 83.7% vs. 76.6% (P=0.345). Subgroup analysis by disease stage revealed pCR rates of 74.3% in stage II gBRCAm pts versus 65.2% in BRCAwt pts (P=0.334), and 72.7% in stage III gBRCAm pts compared to 45.3% in BRCAwt pts (P=0.113).Grade 3 or higher adverse events (AEs) occurred in 50% of gBRCAm pts versus 34.9% of BRCAwt pts (P=0.055), with more frequent neutropenia (32.6% vs. 19.5%, P=0.041), diarrhea (6.1% vs. 1.6%, P=0.079), and immune-related AEs (12.2% vs. 7.4%, P=0.259). There were no significant differences in drug discontinuation rates due to toxicity (28% vs. 22%, P=0.327). Conclusions: Pts with gBRCAm exhibited high pCR rates with the KEYNOTE-522 regimen, achieving pCR rates over 70% even in stage III disease. Further research is needed to optimize treatment strategies in this population, including potential de-escalation approaches.

Estrogen receptor-low (ER-low) breast cancer (BC) present clinicopathological features and disease behavior resembling triple-negative breast cancer, but have been frequently excluded from pivotal trials designed for the latter. Since neoadjuvant pembrolizumab plus chemotherapy (P + CT) is the new standard of care for stage II-III triple-negative breast cancer (TNBC), we aimed to access the effectiveness of this therapy for ER-low tumors. We evaluated patients with ER-low BC included in the Neo-Real/ GBECAM-0123 study, a real-world data study evaluating patients treated with neoadjuvant P + CT since July 2020 across ten cancer centers. The objective of this study was to evaluate the effectiveness of neoadjuvant P + CT through pathologic complete response (pCR). Twenty patients were included in this analysis. Median age was 40 years (range 28–64). Most patients had grade 3 tumors (n = 18, 90

PURPOSEAdjuvant chemotherapy decisions for early-stage hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer remain challenging, requiring a balance between treatment efficacy and avoiding overtreatment. Gene expression signatures, such as the Oncotype DX assay, are valuable tools to predict recurrence risk and guide chemotherapy use. This study estimates the budget impact of incorporating the Oncotype DX test into clinical practice for patients with HR+/HER2- early-stage breast cancer in Brazil's private health care system.METHODSA budget impact analysis was performed using a hybrid decision tree-Markov model with transitions between recurrence-free survival, distant recurrence, acute myeloid leukemia, and death. The eligible population was derived from epidemiologic data. Subgroup analyses included node-negative (N0) patients stratified by age and clinical risk and node-positive (N1) patients stratified by menopausal status. The model assessed direct medical costs over 5 years without applying a discount rate. Two scenarios were analyzed: scenario 1, with progressive market uptake (40%-80% over 5 years), and scenario 2, with universal testing.RESULTSThe introduction of the Oncotype DX test was associated with 5-year cost savings of approximately $19.3 million US dollars (USD; scenario 1) to $26.7 million USD (scenario 2). Incremental costs were observed only in N0 low-risk patients 50 years and younger ($9.5-$16.9 million USD) and premenopausal N1 patients ($2.2-$4.4 million USD).CONCLUSIONIncorporating the Oncotype DX test is expected to optimize chemotherapy recommendations, reduce overtreatment, and generate cost savings in most subgroups. In Brazil's private health care system, the reduction in chemotherapy-related costs is anticipated to fully or partially offset the cost of testing.

Background: The KEYNOTE-522 trial established neoadjuvant pembrolizumab plus chemotherapy (P+CT) followed by adjuvant pembrolizumab as the standard of care for stage II-III triple-negative breast cancer (TNBC). Nevertheless, numerous doubts were raised in clinical practice on how to integrate this regimen with other treatment standards such as adjuvant capecitabine (C) or olaparib (O). This study aims to evaluate treatment patterns and safety outcomes of adjuvant therapies following neoadjuvant P+CT using real-world data (RWD). Methods: The multicentric Neo-Real study evaluates patients with TNBC treated with neoadjuvant P+CT since July 2020 across ten cancer centers. The objective of this analysis is to describe the treatment patterns in the real-world and to analyze the safety associated with these treatments, focusing on grade ≥ 3 adverse events (AE) and rates of drug discontinuation due to AE. Results: To date, 410 patients have been included in the Neo-Real study, with 349 having a pathologic report following surgery and 185 concluding all the adjuvant therapy phase. Median age was 43 years; 69.5% had stage II and 25.8% stage III disease. Pathologic complete (pCR) response was achieved in 62.5% (n = 218) of patients and residual disease was found in 37.5% (n = 131). Among patients with pCR, 14% (n = 31) did not receive any adjuvant therapy, and 86% (n = 187) received Pembrolizumab alone (P). Among those with residual disease and a BRCA wild-type/unknown status (n=114), 26.3% (n = 30) received adjuvant P alone, 54.4% (n = 62) received P plus capecitabine (P+C), 10.5% (n = 12) capecitabine alone, 4.4% (n = 5) other regimens (including clinical trials), and 4.4% (n = 5) received no adjuvant therapy. Among those with a BRCA mutation and residual disease (n=12), 75% (n = 9) received pembrolizumab plus olaparib (P+O), 16.7% (n = 2) P+C, and 8.3% (n = 1) olaparib alone. Rates of grade ≥ 3 AE were 6.3% with P, 16.3% with P+C, and 14.3% with P+O (P=0.057). The most common grade ≥ 3 AE were immune-related AE (6.3%) with P, diarrhea (6.1%) and hand-foot syndrome (8.2%) with P+C, and anemia (14.3%) with P+O. Drug discontinuation due to toxicity during adjuvant therapy occurred in 5.4%, 12.7%, and 10% of the cases, respectively (P=105). The immune-related grade ≥ 3 AE with adjuvant P consisted of endocrine disorders (2.8%), hepatitis (1.4%), pneumonitis (0.7%), colitis (0.7%), arthritis (0.7%), and skin toxicity (0.7%). Notably, considering all the course of pre- and post-surgery therapy, 23.7% of the immune-related AE occurred during the adjuvant phase. Conclusions: In a real-world scenario, most patients treated with neoadjuvant chemoimmunotherapy continued adjuvant pembrolizumab after achieving pCR, while adjuvant capecitabine and adjuvant olaparib were frequently used in combination with pembrolizumab for those of residual disease. Combined adjuvant strategies showed higher rates of grade ≥ 3 AE and drug discontinuation. The efficacy of the combined adjuvant strategies remains to be determined. Citation Format: Renata Bonadio, Isadora Sousa, Flávia Balint, Ana Carolina Comini, Monique Tavares, Fernanda Madasi, Jose Bines, Rafael Ferreira, Daniela Rosa, Candice Santos, Zenaide Souza, Daniele Assad-Suzuki, Júlio Araújo, Débora Gagliato, Carlos Henrique dos Anjos, Bruna Zucchetti, Anezka Ferrari, Mayana de Brito, Renata Cangussu, Maria Marcela Monteiro, Paulo M. Hoff, Laura Testa, Maria del Pilar Estevez-Diz, Romualdo Barroso-Sousa. Treatment Patterns and Safety of Adjuvant Therapy After Chemoimmunotherapy for Early-Stage Triple-Negative Breast Cancer in a Real-World Scenario: The Neo-Real Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-11-14.

BACKGROUND:In pivotal CDK4/6 inhibitor (CDK4/6i) adjuvant trials, most patients received chemotherapy (CT). However, the role of CDK4/6i in patients spared CT by a genomic signature remains unclear. We investigated the proportion of patients without genomic CT indication but eligible for adjuvant abemaciclib or ribociclib, and estimated their potential benefit from CDK4/6i. METHODS:This retrospective, real-world study included patients with T1-T3, N0-N1, HR+/HER2- early breast cancer (eBC) who underwent Oncotype DX (ODX) testing (2005-2024) at nine Brazilian institutions. Genomic CT indication followed TAILORx and RxPONDER; CDK4/6i eligibility followed MonarchE and NATALEE. Primary endpoints were 5-year invasive disease-free survival (iDFS) and distant disease-free survival (DDFS) among patients eligible for CDK4/6i, without genomic CT indication, treated with endocrine therapy (ET) alone. RESULTS:Among 922 patients, ODX showed low (<11), intermediate (11-25), and high (>25) genomic risk in 170 (18.4 %), 585 (63.5 %), and 167 (18.1 %), respectively. Overall, 24 (2.6 %) and 120 (13 %) were eligible for abemaciclib and ribociclib, respectively, had no CT indication, and received ET alone. In these patients (median follow-up: 57.8 and 66.4 months), 5-year iDFS and DDFS were 100 %. CONCLUSIONS AND RELEVANCE:HR+/HER2- eBC patients eligible for CDK4/6i but spared CT by ODX are a minority and have excellent outcomes with ET alone. This highlights the potential benefits of integrating genomic and clinical risk stratification to refine therapeutic decision-making regarding the need for CDK4/6i.